DESCRIPTION (Applicant's Abstract): Beta-Catenin is a bifunctional molecule that mediates the connection between the cell surface adhesion molecule Ecadherin and the acting cytoskeleton and also is a partner of T cell factor (TCF) family molecules in forming a heterodimeric transcription factor that mediates signaling from Wnt receptors. beta-Catenin signaling is activated in many cancers by mutation of beta-catenin or by inactivation of beta-catenin-binding molecules. The effects of these oncogenic events are to decrease intracytoplasmic degradation and increase the availability of beta-catenin to carry out its transcriptional function. We have found mutations of the beta-catenin gene in primary prostate cancer tissues, thereby showing that beta-catenin signal transduction is activated in at least some prostate cancer cases. A second potential mechanism for beta-catenin activation in prostate cancer is loss of E-cadherin expression that occurs in approximately half of prostate cancers and is associated with poor prognosis. Our preliminary data suggest that one mechanism by which beta-catenin contributes to prostate cancer promotion and progression is by interacting with the androgen receptor and increasing transcriptional activation by androgen, the essential hormone for prostate cancer growth. Our hypothesis is that beta-catenin activation contributes to prostate cancer progression in part by augmenting androgen-driven gene transcription. This proposal focuses on determining the mechanism of molecular interaction between beta-catenin and androgen receptor. The experiments will attempt to demonstrate a direct interaction between recombinant androgen receptor and beta-catenin proteins. We will map the regions of interaction by deletion analysis and site-directed mutagenesis. We will also determine if E-cadherin binding interferes directly with the region of beta-catenin that binds to androgen receptor. These experiments will establish a linkage between steroid hormone receptor signaling and Wnt signaling. This will set the stage for more comprehensive study of the interaction between androgen action and the Wnt signaling pathway that is mediated by beta-catenin/TCFdriven transcription.